Renal effects and safety between Asian and non‐Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists

Abstract Background Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non‐Asians. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have garnered attention for their potential advantages in renal outcomes. Nevertheless, the impact on diverse ethnic groups remains unknown. Methods The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial registries were searched through August 2023 with the following keywords: nonsteroidal MRAs (finerenone, apararenone, esaxerenone, AZD9977, KBP‐5074), CKD, T2DM, and randomized controlled trial (RCT). A random effects model was used to calculate overall effect sizes. Results Seven RCTs with 14 997 participants were enrolled. Nonsteroidal MRAs reduced urinary albumin to creatinine ratio (UACR) significantly more in Asians than non‐Asians: (weighted mean difference [WMD], −0.59, 95% CI, −0.73 to −0.45, p < .01) vs (WMD, −0.29, 95% CI, −0.32 to −0.27, p < .01), respectively. The average decline of estimated glomerular filtration rate (eGFR) was similar in Asians and non‐Asians (p > .05). Regarding systolic blood pressure (SBP), nonsteroidal MRAs had a better antihypertension performance in Asians (WMD, −5.12, 95% CI, −5.84 to −4.41, p < .01) compared to non‐Asians (WMD, −3.64, 95% CI, −4.38 to −2.89, p < .01). A higher incidence of hyperkalemia and eGFR decrease ≥30% was found in Asians than non‐Asians (p < .01). Conclusions Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non‐Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.

Conclusions: Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.

| INTRODUCTION
Diabetes remains a substantial public health issue, relevant to the changes in human behavior and lifestyle. 1he most common is type 2 diabetes mellitus (T2DM), with estimated prevalence of 10%-25% in Asian countries and 5%-15% in non-Asian countries. 2Among the approximately 463 million adults with diabetes, nearly half live in China, followed by India. 3China also harbors the largest population affected by chronic kidney disease (CKD), 4 despite a prevalence rate of 10.08% lower than global average 13.4%. 5These data highlight the disproportionate global burden of diabetes and CKD, which is more pronounced in Asian than in non-Asian regions.With the aging of the population and the increasing incidence of diabetes, the prevalence of albuminuria and reduced eGFR is still on the rise. 6vidence suggests that overactivation of the mineralocorticoid receptor (MR) leads to inflammation and fibrosis that can drive CKD and cardiovascular disease progression. 7Nonsteroidal MR antagonists (MRAs; including finerenone, apararenone, esaxerenone, AZD9977, and KBP-5074) with higher selectivity than steroidal MRAs are currently in development. 8,9][12] There are many articles on the efficacy and safety of nonsteroidal MRAs, [13][14][15][16] but there is a lack of systematic comparison in different subgroups.Thus, we performed this meta-analysis to evaluate the different renal outcomes and side effects between Asian and non-Asian CKD and T2DM patients when treated with nonsteroidal MRAs.

| Data sources and search strategy
This systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 17The protocol is available from the International Database of Prospectively Registered Systematic Reviews (PROSPERO: CRD42023445719).
A systematic literature search of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial register centers (http://www.clinicaltrials.gov)was performed for relevant clinical trials published until 28 August 2023, without language restrictions.The following Medical Subject Headings (MeSH) terms and text words were used in different search combinations: nonsteroidal mineralocorticoid receptor antagonists (finerenone, apararenone, esaxerenone, AZD9977, KBP-5074), chronic renal insufficiency, type 2 diabetes mellitus, and randomized controlled trials.

| Study selection and criteria
Eligible studies met the following requirements: (a) studies on adults (age ≥ 18 years) with CKD and T2DM; (b) the intervention should be nonsteroidal MRAs, compared with placebo; (c) trials with a duration longer than 12 weeks; (d) trials with at least one of the following outcomes: changes in urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), or systolic blood pressure (SBP) from baseline, incidence of hyperkalemia, eGFR decrease ≥30%, or total adverse events; (e) randomized controlled trial (RCT); (f) trials that reported at least one dispersion measure (confidence interval [CI], SD, or SE) for treatment groups.
Studies were excluded if any of the followings were identified: (a) animal studies, (b) nonoriginal analyses, (c) duplicate studies, (d) trials with nonplacebo control or short duration, (e) not an RCT, and (f) lack necessary data.

| Data extraction and quality assessment
Data extraction was with standardized Excel forms by two independent reviewers, and disagreement was resolved by adjudicator reliance on the method, calibration, and traceability.Authors of articles were contacted for supplemental information when needed, and the references of selected articles were manually searched for additional relevant articles.The following data were extracted: research characteristics (first author, publication year, sample size, trial duration, treatment, and control), baseline patient characteristics (average age, sex ratio, proportion of Asian subjects, and conditions), and relevant outcomes.GetData Graph Digitizer software (version 2.2.5) was used to extract data presented as graphs.The primary end points were defined as renal outcomes, including the decrease in UACR and eGFR from baseline.The secondary end points consisted of SBP, hyperkalemia, eGFR decrease ≥30%, and total adverse events.
Two independent reviewers assessed the quality of each included study according to the Cochrane Handbook for Systematic Reviews of Interventions. 18The following factors were considered when evaluating the risk of bias: random sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias.The quality of evidence was assessed by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) profiler (GRADE pro) software (version 3.6.1).Details were placed in the Supporting Information (Figures S1-S6).3 | RESULTS

| Eligible studies and study characteristics
As shown in Figure 1, of the 717 studies (687 + 30) retrieved from databases and other sources, seven RCTs finally enrolled with 14 997 participants that met the inclusion criteria.0][21] For non-Asian subjects, four RCTs (14 154 patients) were included. 10,11,22,23Nonsteroidal MRAs were given to experimental groups and control groups received placebo.The detailed baseline characteristics were summarized in Table 1.Among the included trials, one study contained a small sample with only 12 patients in control group, leading to "high risk" for weak evidence.The overall risk of bias was low, and details were presented in Figure 2.

| DISCUSSION
Diabetic nephropathy is the leading cause of chronic and end-stage kidney disease. 24Up to 40% of patients with diabetes are expected to also develop CKD. 25 Previous study indicated that the relationship between lowered eGFR and elevated plasma aldosterone might associated with overactivation of MR. 26 Long-term blockade of the renin-angiotensin system contributed to "aldosterone escape" or "aldosterone breakthrough," a phenomenon that aldosterone levels increased in a subset of patients despite therapy. 27,28Therefore, CKD patients still face a high residual risk. 29MRAs can block both aldosteronedependent and aldosterone-independent MR signaling pathways, bringing direct anti-inflammatory and antifibrosis effects. 30,31Nonsteroidal MRAs have emerged as a new therapeutic tool targeting systemic impact. 32,33Compared with steroidal MRAs, nonsteroidal MRAs show higher selectivity, affinity and more balanced tissue distribution between heart and kidney. 34,35The finding about spironolactone generated the hypothesis that safety and efficacy of MRAs might differ by race. 36Thus, we conducted a meta-analysis to evaluate the different renal outcomes between Asian and non-Asian CKD and T2DM patients treated with nonsteroidal MRAs.
Our results indicated that nonsteroidal MRAs significantly decreased UACR in Asian patients compared with non-Asian patients.The mean level of eGFR did not show obvious difference.As for SBP, nonsteroidal MRAs had a better antihypertension performance in Asians.Regarding safety, the incidence of total adverse events did not show significant differences compared with placebo, neither for Asians nor non-Asians.Hyperkalemia and eGFR decrease ≥30% occurred more frequently in Asian patients treated with nonsteroidal MRAs.Although the incidence of serum potassium >5.5 mmol/L was higher than that in the non-Asian subgroup, there was no death due to hyperkalemia.Notably, even a 30% reduction in eGFR was acceptable depending on the magnitude of the decrease in SBP, and these patients did not present adverse reactions associated with renal function. 37As for hyperkalemia, it is suggested that concomitant use of sodium-glucose cotransporter 2 inhibitor can reduce the risk in Japanese patients treated with esaxerenone. 38  The discrepancy may be explained by the following reasons.First, the dietary habit of Asians tends to high sodium food.Indeed, the dietary factors such as high salt, sugar, and fat, alone or in various permutations, are supposed to promote the onset and development of cardiovascular, renal, and endocrine disorders. 39,40Excessive salt intake triggers renal Rac1 upregulation, followed by increased Sgk1 expressions, a downstream molecule of MR signal, indicating salt-induced activation of Rac1-MR pathway. 41,42In kidney, MR activation promotes the transcription of the basolateral Na + /K + -ATPase and the apical epithelial Na + channel, resulting in the increasing reabsorption of Na + and excretion of K + . 30,43,44Owing to MR blockade, patients receiving MRAs have lower blood pressure and a higher incidence of hyperkalemia. 45Second, there are differences in population allele frequences, leading to MR polymorphism by race.For example, variants in NR3C2 (nuclear receptor superfamily 3, group C, member 2) genotype, which codes the target protein MR, are associated with cardiorenal response to spironolactone. 46,47Besides, Asians possess lower body weight than non-Asians. 48Therefore, the drug doses (amount of drug/kg) of nonsteroidal MRAs are relatively higher in Asian patients.
There are limitations in our study.First, the non-Asian subgroup enrolled multicenter studies that did not eliminate a small proportion of Asians.Although it was not completely comparable, the significance of races had been proved without other predominant variables.
Second, only seven studies with 14 997 subjects were included.Trials from other Asian countries except Japan were not found in the databases, making the Asian participants less representative.Subsequent research should strive to encompass a more diverse demographic within the Asian population.Third, the administration duration of nonsteroidal MRAs varied from 90 days to 3.4 years may cause bias. 49Given these limitations, our results should be interpreted with caution.

| CONCLUSIONS
Our study indicated that nonsteroidal MRAs decreased UACR and SBP significantly greater in Asian CKD and T2DM patients than non-Asian patients.The average decline in eGFR did not show racial preference.
There was no significant difference in total adverse events.However, hyperkalemia and eGFR decrease ≥30% occurred more frequently in Asians, which was acceptable without renal failure or death.Doctors should pay more attention to these early changes in patients taking nonsteroidal MRAs, especially in Asians.In the future, we anticipate research of nonsteroidal MRAs with a particular emphasis on diverse populations and investigating long-term outcomes.Participants can be categorized into various groups, including different doses, sex, and different ranks of proteinuria and eGFR, to enhance the individual management of renal disease.
F I G U R E 8 Forest plot of the odds ratio in the incidence of total adverse events.CI, confidence interval; M-H, Mantel-Haenszel.
Values are reported as n (%), mean ± SD, or median (interquartile range) unless otherwise indicated.Abbreviations: BMI, body mass index; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; IQR, interquartile range; NA, not available; RCT, randomized controlled trial; SBP, systolic blood pressure; T2DM, type Review Manager (version 5.3) was used to perform statistical analysis.Except for 95% confidence interval (CI), we used weighted mean difference (WMD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes.Statistical heterogeneity was assessed using the I 2 test and random effects model.Sensitivity analyses were performed to detect the stability of the comparison results.

F I G U R E 2
Evaluation of the risk of bias.

F
I G U R E 3 (A) Forest plot of the weighted mean difference in the change of urinary albumin to creatinine ratio (UACR) from baseline.(B) Forest plot of the weighted mean difference in the change of urinary albumin to creatinine ratio (UACR) from baseline.(Sensitivity analysis).CI, confidence interval; IV, interval variable.

F
I G U R E 4 Forest plot of the weighted mean difference in the change of estimated glomerular filtration rate (eGFR) from baseline.CI, confidence interval; IV, interval variable.F I G U R E 5 Forest plot of the weighted mean difference in the change of systolic blood pressure (SBP) from baseline.CI, confidence interval; IV, interval variable.
Doctors should adjust dosage of nonsteroidal MRAs or add other medications under comprehensive consideration.Close monitoring of SBP, K + , and eGFR does matter in Asian patients.

F
I G U R E 6 Forest plot of the odds ratio in the incidence of hyperkalemia.CI, confidence interval; M-H, Mantel-Haenszel.F I G U R E 7 Forest plot of the odds ratio in the incidence of estimated glomerular filtration rate (eGFR) decrease ≥30%.CI, confidence interval; M-H, Mantel-Haenszel.
Characteristics of studies reporting the effects of nonsteroidal mineralocorticoid receptor antagonists (MRAs).
of study selection.CNKI, China National Knowledge Infrastructure; RCT, randomized controlled trial.T A B L E 1